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Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-controlled Trials: The Cross Trial Safety Analysis

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Title: Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-controlled Trials: The Cross Trial Safety Analysis


1
Cardiovascular Risk of Celecoxibin6 Randomized
Placebo-controlled TrialsThe Cross Trial Safety
Analysis
  • Scott D. Solomon, MD, Janet Wittes, PhD,
  • Ernest Hawk, MD, MPH for the Celecoxib
  • Cross Trials Safety Analysis Investigators

Manuscript available simultaneously online in
Circulation http//circ.ahajournals.org
2
DISCLOSURES
  • No Disclosures
  • This research was funded entirely by the National
    Cancer Institute

3
Background
  • Observational studies and randomized controlled
    trials have reported increased cardiovascular
    risk associated with cyclooxygenase-2 (cox-2)
    inhibitors (coxibs) 1,2,3,4
  • Strong biologic basis for this risk supported by
    abundant basic research5,6,7
  • Most clinical studies compared coxibs with active
    comparators in short-term arthritis trials

1McGettigan JAMA 2006 2Graham et al. Lancet
2005 3Bresalier et al. NEJM 2005 4Solomon et
al. NEJM 2005 5McAddam et al. PNAS 1999
6Fitzgerald NEJM 2001 7Fitgerald et al. NEJM 2004
4
Background
  • In December 2004, interim results from the
    Adenoma Prevention with Celecoxib (APC) trial
    results led to stopping drug in that trial and
    in 5 other long-term trials comparing celecoxib
    to placebo
  • The Prevention of Sporadic Adenomatous Polyps
    (PreSAP) trial1
  • The Alzheimers Disease Anti-inflammatory
    Prevention Trial (ADAPT)2
  • The MA-27 Breast Cancer Trial,
  • The Celecoxib Diabetic Macular Edema (CDME) trial
  • The Celecoxib/Selenium Trial.
  • FDA hearing resulted in Black Box Warning.
  • Celecoxib is the only available cox-2 inhibitor
    in US.

1 Arber et al. NEJM 2006 2 ADAPT Invest.
PLOS 2006
5
Low Event Rates Lead to Challengesin Risk
Assessment with Coxibs
  • Low precision of the estimates
  • Inability to test observational and RCT data
    suggesting
  • coxib-associated CV risk may be dose related
  • dose and interval may be important in CV risk.1
  • Inability to assess whether CV risk associated
    with celecoxib varies by baseline CV risk

1Solomon et al Circulation 2006
6
Objective
  • To understand more fully the cardiovascular risk
    profile associated with long-term use of
    celecoxib
  • NCI commissioned and funded analysis of long-term
    placebo controlled trials

7
Selection of Studies
  • Randomized, double-blind, placebo-controlled
    trials
  • Planned follow-up of at least 3 years
  • Source documentation available for adjudication
  • 4 trials APC and PreSAP fulfilled these
    criteria
  • ADAPT
  • MA-27
  • CDME
  • Celecoxib/Selenium Trial

8
Methodology
  • Each study submitted patient-level data
  • Baseline data
  • Outcomes
  • Adverse events
  • A blinded adjudication team identified all
    potential cardiovascular events from broad list
    of SAEs and AEs
  • Requested source documentation for all relevant
    events
  • All potential cardiovascular events were
    adjudicated by two reviewers masked to treatment
    allocation
  • Categorized all deaths
  • Adjudicated all non-fatal events

Endpoint Definitions Solomon et al. NEJM 2005
9
Endpoints
  • The following endpoints were adjudicated
  • Death (cardiovascular or non-cardiovascular)
  • Myocardial Infarction
  • Stroke
  • Hospitalization for heart Failure
  • Thromboembolic event
  • Other cardiovascular
  • Primary endpoint
  • CV death, MI, stroke, heart failure or
    thromboembolic event

10
Statistical Analysis
  • Intention-to-treat
  • Time-to-event analyses for each study
  • Calculated incidence of each outcome, rate (per
    1000 pt-yrs) by Rx group
  • Cox models and KM curves
  • Pooled (meta) analysis
  • Estimated hazard ratios calculated from the
    average of the log-hazard ratio for each
    individual trial weighted by the inverse of its
    variance
  • Sensitivity of method assessed by standard
    Mantel-Haenszel pooled odds ratios and Cox models
    stratified by study.
  • Analyses adjusted for baseline cardiovascular
    risk
  • Pooled analyses assessed overall risk and dosing
    regimen-related risk

11
Dose and Baseline Risk
  • Studies were grouped according to dose regimen
  • 400mg once daily (2 studies)
  • 200mg twice daily (3 studies)
  • 400mg twice daily (2 studies)
  • We tested for interaction between dose regimen
    and celecoxib risk
  • We created a 3-category risk score using a
    modified Framingham Risk model conforming to the
    availability of data from these studies
  • Low No known risk factor
  • Moderate One of following , age gt 75,
    hypertension, hyperlipidemia, current smoker,
    low-dose ASA
  • High Diabetes, prior CV disease, or 2 risk
    factors in moderate category
  • We tested for interaction between baseline risk
    and celecoxib-related risk.

12
Placebo-Controlled Trials
Study N Sponsor Disease being Studied Celecoxib Dose Planned follow-up time
APC 2035 NCI and Pfizer Colorectal polyps Celecoxib 200mg BID, celecoxib 400mg BID, or placebo 3 Years
PreSAP 1561 Pfizer Colorectal Polyps Celecoxib 400mg QD or placebo 3 Years
MA27 1635 NCI, NCI Canada, Pfizer Breast Cancer Recurrence celecoxib 400 mg BID or placebo 3 Years
ADAPT 1809 NIA Alzheimers disease and cognitive decline Celecoxib 200mg BID or Naproxen sodium 220 mg BID, or placebo Up to 7 years
CDME 86 NEI Diabetic Retinopathy Celecoxib 200mg BID or placebo 3 Years
Cel/Sel 824 NCI Colorectal polyps Celecoxib 400 mg QD or placebo 3-5 Years
13
Baseline Characteristics ()
ADAPT ADAPT APC APC CDME MA27 MA27 PreSAP Cel/Sel Total
enrolled Pt-Years 1809 3530 1809 3530 2035 6234 2035 6234 86 101 1635 695 1635 695 1561 4141 824 1369 7950 16070
Age, mean (SD) 75 4 59 10 59 10 59 9 59 9 59 9 64 9 60 10 63 9 64 10
Male 54 68 68 62 62 62 0 66 68 50
White race 97 92 92 67 67 67 94 89 96 93
Diabetes 7.4 9.5 9.5 100 100 100 6.1 10 7.5 9.2
HTN or med 40 41 41 62 62 62 34 37 36 38
Hyperlipidemia or med 33 38 38 55 55 55 17 17 33 28
Current smoker 3 17 17 ? ? ? ? 24 16 14
Low-dose ASA use 50 31 31 62 62 62 14 17 45 31
Prior CV event 13 14 14 1.2 1.2 1.2 7 13 14 12
Low CV risk 14 24 24 0 0 0 50 32 19 28
Moderate CV risk 26 29 29 0 0 0 23 31 31 27
High CV risk 59 47 47 100 100 100 27 37 51 45
14
Event Numbers, Rates and Hazard Ratios
Events (Event Rate per 1000/pt-yrs) Events (Event Rate per 1000/pt-yrs) Events (Event Rate per 1000/pt-yrs) Events (Event Rate per 1000/pt-yrs) Hazard Ratio
400mg QD placebo celecoxib celecoxib celecoxib
PreSAP 12/628 (7.2) 12/628 (7.2) 23/933 (9.4) 23/933 (9.4) 1.3 (0.6, 2.5)
Cel/Sel 8/410 (11.8) 8/410 (11.8) 7/414 (10.3) 7/414 (10.3) 0.9 (0.3, 2.4)
400mg QD Pooled 20/1038 (8.6) 20/1038 (8.6) 30/1347 (9.6) 30/1347 (9.6) 1.1 (0.6, 2.0)
200mg BID
ADAPT 18/1083 (8.6) 18/1083 (8.6) 18/725 (12.8) 18/725 (12.8) 1.5 (0.8, 2.9)
APC 8/679 (3.9) 8/679 (3.9) 20/685 (9.7) 20/685 (9.7) 2.5 (1.1, 5.7)
200mg BID Pooled 29/1809 (6.9) 29/1809 (6.9) 38/1450 (10.8) 38/1450 (10.8) 1.8 (1.1, 3.1)
400mg BID 400mg BID 400mg BID 400mg BID 400mg BID 400mg BID
APC 8/679 (3.9) 8/679 (3.9) 8/679 (3.9) 27/671 (13.4) 3.6 (1.6, 8.0)
MA-27 3/817 (8.7) 3/817 (8.7) 3/817 (8.7) 6/818 (17.2) 1.8 (0.4, 7.3)
400mg BID pooled 11/1496 (4.6) 11/1496 (4.6) 11/1496 (4.6) 33/1489 (13.9) 3.1 (1.5, 6.1)
CDME Not included in this table because of
extremely low event rates
Solomon et al. Circulation 2008
15
Hazard Associated with Celecoxib at Various
DosesStratified by Study and low-dose ASA use
and Adjusted for Baseline CV Risk
400 mg bid
3.1 (1.5, 6.1)
Dose-regimen effect P 0.0005
Regimen
1.8 (1.1, 3.1)
200 mg bid
Celecoxib
1.1 (0.6, 2.0)
400 mg
qd
1.6 (1.1, 2.3)
Overall
0.5
0.7
0.9
1
2
3
4
5
6
0.5
0.7
0.9
1
2
3
4
5
6
Hazard Ratio CV Death, MI, Stroke, HF or
thrombo-embolic event
Solomon et al. Circulation 2008
16
Composite Outcomes (Hazard ratio and 95 CI)
400mg QD 200mg BID 400mg BID
CV Death 0.5 (0.2, 1.7) 1.8 (0.5, 6.2) 6.5 (0.8, 54)
MI MI 1.0 (0.5, 2.1) 2.1 (1.0, 4.1) 3.4 (1.2, 9.6)
Stroke Stroke 1.0 (0.5, 1.9) 1.6 (0.9, 3.0) 2.9 (1.3, 6.6)
HF HF 1.1 (0.6, 2.1) 1.7 (1.0, 3.1) 2.7 (1.3, 5.6)
Embolic event Embolic event Embolic event 1.1 (0.6, 2.0) 1.8 (1.1, 3.1) 3.1 (1.5, 6.1)
Any CV Event Any CV Event 1.3 (0.9, 1.9) 1.4 (1.0, 1.8) 1.6 (1.1, 2.3)
Stratified by study and baseline aspirin use and
adjusted for baseline risk
Solomon et al. Circulation 2008
17
Celecoxib Regimen and Baseline Cardiovascular Risk
Baseline Risk Dose Regimen Interaction p 0.034
HR (95 CI)
High Risk
High Risk
3.5 (1.9,6.4)
400 bid
400 bid
2.3 (1.5, 3.4)
200 bid
200 bid
1.5 (1.2, 1.9)
400
qd
400
qd
Moderate Risk
1.7 (0.9,3.2)
400 bid
Celecoxib Regimen and pre-treatment
Cardiovascular Risk
1.4 (1.0, 2.2)
200 bid
1.2 (1.0,1.5)
400
qd
400
qd
Low Risk
0.9 (0.3, 2.6)
400 bid
0.9 (0.4, 1.9)
200 bid
1.0 (0.7, 1.4)
400qd
Hazard Ratio CV Death, MI, Stroke, HF or
Thromboembolic Event
Solomon et al. Circulation 2008
18
Prespecified Subgroups
P-Interaction p 0.37 p 0.64 p 0.54 p
0.89 p 0.17 p 0.09 p 0.40 p 0.57
Non-Smoker
Current Smoker
No Diabetes
Diabetes
No Hyperlipidemia
Hyperlipidemia
No Hypertension
Hypertension
No CV Event
CV Event History
No Low Dose ASA
Low Dose ASA
Non-White
White
Female
Male
0.3
0.4
0.6
0.8
1
2
3
4
5
6
Hazard Ratio
Solomon et al. Circulation 2008
19
Limitations and Caveats
  • None of the trials included in this analysis was
    designed or powered with the intent of assessing
    cardiovascular risk.
  • Doses tested higher than those typically used in
    osteoarthritis patients.
  • recommended doses in rheumatoid arthritis, acute
    pain and dysmenorrhea, FAP.
  • These data provide the strongest evidence of a
    dose-related risk
  • While our data support differential risk based on
    dosing interval, wide confidence intervals
    suggest we cannot rigorously exclude hazard at
    the 400mg once daily dose.
  • These data do not address the cardiovascular risk
    of doses lower than those tested or of other
    non-selective NSAIDs.

20
Conclusions (1)
  • A pooled analysis of six randomized trials
    comparing celecoxib to placebo, with over 16,000
    patient-years of follow-up, shows an overall
    increase in cardiovascular risk, with evidence
    for differences in risk based on the dose and
    dose-regimen of celecoxib.
  • The data showed evidence of an interaction
    between baseline cardiovascular risk and the
    effect of celecoxib, suggesting that patients at
    highest baseline risk had an increased relative
    risk for celecoxib-related adverse cardiovascular
    events.

21
Conclusions (2)
  • Our observation that baseline risk influences the
    cardiovascular risk associated with celecoxib may
    provide a measure of comfort in prescribing the
    drug in patients with very low baseline risk, and
    would argue for more caution in prescribing the
    drug in patients with higher baseline risk.
  • Since celecoxib remains the only coxib available
    in the United States, and is the most commonly
    used coxib worldwide, these data should help
    guide rational clinical decisions regarding
    celecoxib use.

22
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23
Composite KM Curves
0.050
Combined studies (excluding CDME)
0.045
Log-rank p-value (3 df) 0.026
0.040
0.035
0.030
Probability of event
0.025
0.020
0.015
0.010
0.005
0.000
0
6
12
18
24
30
36
Months of follow-up
Sample size
1489
990
714
654
648
645
641
C 400 bid
1411
1342
1258
1157
1033
894
768
C 200 bid
1347
1231
1134
1042
939
841
514
C 400 QD
Placebo
3617
2943
2453
2168
1894
1598
1196
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